tbuckley/cabot-search huggingface dataset:
Physical activity: short-term pain with so much to gain!
Authors: Myles Calder Murphy, Andrea Britt Mosler
Journal: British Journal of Sports Medicine (2022)

The amethopterin-resistant bacterium <i>Streptococcus faecium</i> var. <i>durans</i>/A<sub>k</sub> (SF/A<sub>k</sub>) synthesizes at least two species of tetrahydrofolate dehydrogenase. The more abundant species, designated <i>folate reductase</i>, catalyzes the pyridine nucleotide-dependent reductions of folate and dihydrofolate. It has been purified 68-fold and resolved from a minor species. The minor species of enzyme apparently is the <i>specific dihydrofolate reductase</i>, which is prevalent in the amethopterin-sensitive parent strain, <i>S. faecium</i> var. <i>durans</i>/O (SF/O), and mediates only dihydrofolate reduction. Folate reductase has an estimated molecular weight of 22,500. Like the tetrahydrofolate dehydrogenases of animal sources, it catalyzes dihydrofolate reduction more rapidly than folate reduction. Several kinetic characteristics of folate and dihydrofolate reduction were determined. Similarities between the folate reductase of SF/A<sub>k</sub> and the nonbacterial tetrahydrofolate dehydrogenases pointed to the usefulness of this bacterial folate reductase in evaluating the reductase-inhibitory activity of new chemicals synthesized as potential chemotherapeutic agents. Analyses of the inhibition of folate and dihydrofolate reduction by amethopterin and by a new quinazoline antifolate, <i>N</i>-[<i>p</i>-[[(2,4-diamino-5-methyl-6-quinazolinyl)methyl]amino]benzoyl]-L-aspartic acid, designated methasquin, suggested that the latter may be beneficial clinically and, perhaps, more effective than amethopterin. The enzyme-methasquin interaction is slightly firmer than the enzyme-amethopterin interaction and, unlike the latter, is relatively independent of experimental conditions.
SLIT2 promoter hypermethylation-mediated SLIT2-IT1/miR-218 repression drives leukemogenesis and predicts adverse prognosis in myelodysplastic neoplasm
Authors: Ting-juan Zhang, Zi-jun Xu, Xiang-mei Wen, Yu Gu, Ji-chun Ma, Qian Yuan, Jiang Lin, Jing-dong Zhou, Jun Qian
Journal: Leukemia (2022)
One-off physiotherapy and at-home exercise are effective in treating shoulder pain
Authors: Helen Saul, Deniz Gursul, Sally Hopewell
Journal: BMJ (2022)

The study Hopewell S, Keene DJ, Marian IR, et al. Progressive exercise compared with best practice advice, with or without corticosteroid injection, for the treatment of patients with rotator cuff disorders (GRASP): a multicentre, pragmatic, 2 × 2 factorial, randomised controlled trial. Lancet 2021;398:416-28. To read the full NIHR Alert, go to: https://evidence.nihr.ac.uk/alert/one-off-physiotherapy-session-effective-for-shoulder-pain/
Death and the bogus contract between doctors and patients: what is in the patient’s best interests?
Authors: Martin G Ronchetti
Journal: BMJ (2022)

Background/Aim: Prognosis plays a vital role in head and neck squamous cell carcinoma (HNSCC) patient management and decision-making. This study aimed to identify the role of BP180 as a prognostic factor in HNSCC. Patients and Methods: Protein expression of bullous pemphigoid antigen II (BP180) was verified by immunohistochemistry (IHC) in a tissue microarray study of 202 cases. Results: IHC analysis revealed that protein expression of BP180 among HNSCC patients differed significantly in the presence and absence of neural invasion, and according to T status in laryngeal and pharyngeal cancer subgroups. Overall survival and multivariate analysis showed that positive BP180-IHC and advanced clinical stage were significant independent positive predictors of mortality in HNSCC patients. In addition, in the oral cancer subgroup, independent positive predictors were positive BP180-IHC, advanced N status and neural invasion. In laryngeal and pharyngeal cancer subgroups, predictors were positive BP180-IHC and advanced clinical stage. Conclusion: BP180 is a prognostic factor in head and neck squamous cell carcinoma.
A truncated derivative of FGFR1 kinase cooperates with FLT3 and KIT to transform hematopoietic stem cells in syndromic and de novo AML
Authors: Baohuan Cai, Yun Liu, Yating Chong, Stephanie Fay Mori, Atsuko Matsunaga, Hualei Zhang, Xuexiu Fang, Chang-Sheng Chang, John K. Cowell, Tianxiang Hu
Journal: Molecular Cancer (2022)

Myeloid and lymphoid malignancies associated with chimeric FGFR1 kinases are the hallmark of stem cell leukemia and lymphoma syndrome (SCLL). In all cases, FGFR1 kinase is constitutively phosphoactivated as a result of chromosome translocations, which lead to acquisition of dimerization motifs in the chimeric proteins. Recently, we demonstrated that these chimeric kinases could be cleaved by granzyme B to generate a truncated derivative, tnFGFR1, which localized exclusively into the nucleus and was not phosphorylated.Stem cell transduction and transplantation in syngeneic mice was used to assess the transforming ability of tnFGFR1 in bone marrow stem cells, and RPPA and RNA-Seq was used to examine the related signaling pathways and regulated target genes.For the first time, we show that this non-classical truncated form of FGFR1 can independently lead to oncogenic transformation of hematopoietic stem cells in an animal model in vivo. These leukemia cells show a mixed immunophenotype with a B-cell B220 + Igm- profile in the majority of cells and Kit+ in virtually all cells, suggesting a stem cell disease. tnFGFR1, however, does not activate classic FGFR1 downstream signaling pathways but induces a distinct profile of altered gene expression with significant upregulation of transmembrane signaling receptors including FLT3 and KIT. We further show that de novo human AML also express tnFGFR1 which correlates with upregulation of FLT3 and KIT as in mouse leukemia cells. ChIP analysis demonstrates tnFGFR1 occupancy at the Flt3 and Kit promoters, suggesting a direct transcriptional regulation. Cells transformed with tnFGFR1 are insensitive to FGFR1 inhibitors but treatment of these cells with the Quizartinib (AC220) FLT3 inhibitor, suppresses in vitro growth and development of leukemia in vivo. Combined treatment with FGFR1 and FLT3 inhibitors provides increased survival compared to FGFR1 inhibition alone.This study demonstrates a novel model for transformation of hematopoietic stem cells by chimeric FGFR1 kinases with the combined effects of direct protein activation by the full-length kinases and transcriptional regulation by the truncated nuclear tnFGFR1 derivative, which is associated with GZMB expression levels. Genes significantly upregulated by tnFGFR1 include Flt3 and Kit which promote a leukemia stem cell phenotype. In human AML, tnFGFR1 activation leads to increased FLT3 and KIT expression, and higher FLT3 and GZMB expression levels are associated with an inferior prognosis. These observations provide insights into the relative therapeutic value of targeting FGFR1 and FLT3 in treating AML with this characteristic gene expression profile.
Cross-platform analysis reveals cellular and molecular landscape of glioblastoma invasion
Authors: Ann T Chen, Yang Xiao, Xiangjun Tang, Mehdi Baqri, Xingchun Gao, Melanie Reschke, Wendy C Sheu, Gretchen Long, Yu Zhou, Gang Deng, Shenqi Zhang, Yanxiang Deng, Zhiliang Bai, Dongjoo Kim, Anita Huttner, Russell Kunes, Murat Günel, Jennifer Moliterno, W Mark Saltzman, Rong Fan, Jiangbing Zhou
Journal: Neuro-Oncology (2022)

Abstract Background Improved treatment of glioblastoma (GBM) needs to address tumor invasion, a hallmark of the disease that remains poorly understood. In this study, we profiled GBM invasion through integrative analysis of histological and single-cell RNA sequencing (scRNA-seq) data from 10 patients. Methods Human histology samples, patient-derived xenograft mouse histology samples, and scRNA-seq data were collected from 10 GBM patients. Tumor invasion was characterized and quantified at the phenotypic level using hematoxylin and eosin and Ki-67 histology stains. Crystallin alpha B (CRYAB) and CD44 were identified as regulators of tumor invasion from scRNA-seq transcriptomic data and validated in vitro, in vivo, and in a mouse GBM resection model. Results At the cellular level, we found that invasive GBM are less dense and proliferative than their non-invasive counterparts. At the molecular level, we identified unique transcriptomic features that significantly contribute to GBM invasion. Specifically, we found that CRYAB significantly contributes to postoperative recurrence and is highly co-expressed with CD44 in invasive GBM samples. Conclusions Collectively, our analysis identifies differentially expressed features between invasive and nodular GBM, and describes a novel relationship between CRYAB and CD44 that contributes to tumor invasiveness, establishing a cellular and molecular landscape of GBM invasion.
Endoscopy International Open – recently published
Journal: Endoscopy (2019)

Comment on: EUS-guided pancreatic radiofrequency ablation: preclinical comparison of two currently available devices in a pig modelEndosc Int Open 2019; 07(02): E138-E143DOI: 10.1055/a-0668-5653 Comment on: Linked color imaging improves the endoscopic visibility of gastric mucosal cancersEndosc Int Open 2019; 07(02): E164-E170DOI: 10.1055/a-0733-7086 Comment on: Durability and long-term outcomes of direct EUS-guided gastroenterostomy using lumen-apposing metal stents for gastric outlet obstructionEndosc Int Open 2019; 07(02): E144-E150DOI: 10.1055/a-0799-9939
Highlights of This Issue
Journal: Clinical Cancer Research (2019)

Cancers with an immunosuppressive tumor microenvironment (TME) are less likely to respond to immunotherapy. In this study, Bhatia and colleagues treated ten Merkel cell carcinoma patients with intratumoral G100, a TLR4 agonist. G100 treatment led to an immunologically active TME with increased infiltration and activation of CD8+ and CD4+ T cells. Two out of three patients with locoregional disease showed sustained responses greater than 41 months. Of seven patients with metastatic disease, two showed partial responses lasting at least 33 months. Treatment was well-tolerated with mild local inflammation and no systemic toxicity. Intratumoral G100 warrants additional investigation, both as a monotherapy and in combination with other agents.Identifying patients who are most likely to respond to adjuvant therapy remains a major challenge in the treatment of many cancers, including renal cell carcinoma (RCC). George and colleagues investigated correlations between improved disease-free survival (DFS) and single nucleotide polymorphisms (SNPs) in angiogenesis- and hypoxia-related genes. SNPs in VEGFR1, VEGFR2, and eNOS were associated with improved DFS in patients with high-risk RCC who received adjuvant sunitinib, a VEGF inhibitor. This study identified SNPs that should be further tested for their potential to help identify the patients most likely to benefit from adjuvant sunitinib treatment, while reducing unnecessary toxicity risk in others.The effective detection of metastatic lesions is often not feasible until a cancer has become advanced. Hausner and colleagues describe a novel approach to detect metastases using PET imaging. An integrin αvβ6 binding peptide was radiolabeled with 4-[18F]fluorobenzoic acid ([18F]αvβ6-BP); this peptide was found to bind specifically to integrin αvβ6, which is uniquely expressed on cancer cells, in in vitro and in vivo models. The authors extended their study to several patients, concluding that [18F]αvβ6 -BP was effective in revealing primary tumors and metastases smaller than 1 cm in several organs (including brain, bone, liver, and lung) using PET imaging. This molecule has the potential to vastly improve the early detection of metastatic disease.Despite harboring actionable mutations, many cancers ultimately develop resistance to targeted therapy. Suzawa and colleagues examined clinical and genomic data from 113 lung cancer patients harboring METex14 alterations to identify mechanisms through which resistance to MET tyrosine kinase inhibitors occur. Patients were more likely to harbor concurrent activating KRAS mutations in METex14 cancers than in cancers dependent on other driver alterations. KRAS mutation or amplification was found to cause resistance to MET inhibition through constitutive activation of the RAS/ERK pathway. Combining MET inhibition with EGFR/ERBB2 inhibition successfully reduced the growth of dual-mutant cells both in vitro and in vivo, providing a potential therapeutic combination to combat resistance to MET inhibitors in lung cancer patients.
Highlights of This Issue
Journal: Clinical Cancer Research (2019)

Hyperprogression (HP) is a paradoxical boost in tumor growth described in a subset of patients treated with immune checkpoint inhibitors that has ignited an international debate on whether this phenomenon is true or only representative of a worse prognosis. Mimicking HP in preclinical models with distinctive genetic profile allowed Lo Russo and colleagues to uncover a critical role of innate immunity in this process that involves the interaction of anti-PD-1 antibody-Fc with FcR on M2-like macrophages. A distinctive immunophenotype of HP tumors characterized by clustered macrophages with epithelioid morphology is potentially able to predict HP.Anti-PD-1 antibodies are approved for non-small cell lung cancer treatment, yet only one-quarter of patients benefit from this therapy. PD-L1 labelling and mutational tumor burden could help the clinician to predict outcome; however, optimal predictive biomarkers are lacking. This study by Richard and colleagues demonstrates that exome analysis before initiation of nivolumab therapy can be highly predictive of PFS and OS when analyzed in multiple dimensions, rather than using only mutational tumor burden. These findings have far-reaching implications in this age of precision medicine for an efficient immunotherapy and should increase the interest of complex analysis of exome for precision medicine in immuno-oncology.Urothelial carcinomas of the upper tract (UTUC) and bladder (UCB) exhibit similar histologic appearance but have distinct clinical and molecular characteristics. To investigate genomic differences between UTUC and UCB, Audenet and colleagues leveraged a prospective molecular characterization initiative to analyze 649 urothelial carcinomas using a targeted next-generation sequencing (NGS) platform. They identified significant differences in the prevalence of common genomic alterations. However, in individual patients with a history of both tumors, the UCB and UTUC were always clonally related. Furthermore, targeted NGS was a robust methodology for identifying UTUC patients in need of germline analysis for Lynch syndrome.The bifunctional roles of SCAN-Zinc finger transcription factor MZF1 in carcinogenesis remains unclear. Based on their previous observations that the garlic-derived compound diallyl trisulfide (DATS) suppresses gastric cancer (GC) growth and enhances its chemosensitivity through epigenetic upregulation of MT2A to attenuate NF-κB activation, Lin and colleagues found an association of MZF1 with MT2A in human GC cell lines and primary tumors, and reveal that MT2A recruits MZF1 to form MT2A/MZF1 complex binding to NFKBIA promoter to establish an “MT2A/MZF1-NF-κB” pathway in suppressing gastric carcinogenesis and enhancing GC chemosensitivity. MT2A/MZF1 thus represents a diagnostic marker and a therapeutic target for GC.
Localization-adjusted diagnostic performance and assistance effect of a computer-aided detection system for pneumothorax and consolidation
Authors: Sun Yeop Lee, Sangwoo Ha, Min Gyeong Jeon, Hao Li, Hyunju Choi, Hwa Pyung Kim, Ye Ra Choi, Hoseok I, Yeon Joo Jeong, Yoon Ha Park, Hyemin Ahn, Sang Hyup Hong, Hyun Jung Koo, Choong Wook Lee, Min Jae Kim, Yeon Joo Kim, Kyung Won Kim, Jong Mun Choi
Journal: npj Digital Medicine (2022)

Abstract While many deep-learning-based computer-aided detection systems (CAD) have been developed and commercialized for abnormality detection in chest radiographs (CXR), their ability to localize a target abnormality is rarely reported. Localization accuracy is important in terms of model interpretability, which is crucial in clinical settings. Moreover, diagnostic performances are likely to vary depending on thresholds which define an accurate localization. In a multi-center, stand-alone clinical trial using temporal and external validation datasets of 1,050 CXRs, we evaluated localization accuracy, localization-adjusted discrimination, and calibration of a commercially available deep-learning-based CAD for detecting consolidation and pneumothorax. The CAD achieved image-level AUROC (95% CI) of 0.960 (0.945, 0.975), sensitivity of 0.933 (0.899, 0.959), specificity of 0.948 (0.930, 0.963), dice of 0.691 (0.664, 0.718), moderate calibration for consolidation, and image-level AUROC of 0.978 (0.965, 0.991), sensitivity of 0.956 (0.923, 0.978), specificity of 0.996 (0.989, 0.999), dice of 0.798 (0.770, 0.826), moderate calibration for pneumothorax. Diagnostic performances varied substantially when localization accuracy was accounted for but remained high at the minimum threshold of clinical relevance. In a separate trial for diagnostic impact using 461 CXRs, the causal effect of the CAD assistance on clinicians’ diagnostic performances was estimated. After adjusting for age, sex, dataset, and abnormality type, the CAD improved clinicians’ diagnostic performances on average (OR [95% CI] = 1.73 [1.30, 2.32]; p &lt; 0.001), although the effects varied substantially by clinical backgrounds. The CAD was found to have high stand-alone diagnostic performances and may beneficially impact clinicians’ diagnostic performances when used in clinical settings.
Requirement for TP73 and genetic alterations originating from its intragenic super-enhancer in adult T-cell leukemia
Authors: Jolynn Zu Lin Ong, Rui Yokomori, Regina Wan Ju Wong, Tze King Tan, Ryuzo Ueda, Takashi Ishida, Shinsuke Iida, Takaomi Sanda
Journal: Leukemia (2022)
Retraction Note: Exosome-transmitted miR-128-3p increase chemosensitivity of oxaliplatin-resistant colorectal cancer
Authors: Tong Liu, Xin Zhang, Lutao Du, Yunshan Wang, Xiaoming Liu, Hui Tian, Lili Wang, Peilong Li, Yinghui Zhao, Weili Duan, Yujiao Xie, Zhaowei Sun, Chuanxin Wang
Journal: Molecular Cancer (2022)

This article has been retracted. Please see the Retraction Notice for more detail: https://doi.org/10.1186/s12943-019-0981-7.
PTPRO represses colorectal cancer tumorigenesis and progression by reprogramming fatty acid metabolism
Authors: Weixing Dai, Wenqiang Xiang, Lingyu Han, Zixu Yuan, Renjie Wang, Yanlei Ma, Yongzhi Yang, Sanjun Cai, Ye Xu, Shaobo Mo, Qingguo Li, Guoxiang Cai
Journal: Cancer Communications (2022)

Abstract Background Abnormal expression of protein tyrosine phosphatases (PTPs) has been reported to be a crucial cause of cancer. As a member of PTPs, protein tyrosine phosphatase receptor type O (PTPRO) has been revealed to play tumor suppressive roles in several cancers, while its roles in colorectal cancer (CRC) remains to be elucidated. Hence, we aimed to explore the roles and mechanisms of PTPRO in CRC initiation and progression. Methods The influences of PTPRO on the growth and liver metastasis of CRC cells and the expression patterns of different lipid metabolism enzymes were evaluated in vitro and in vivo. Molecular and biological experiments were conducted to uncover the underpinning mechanisms of dysregulated de novo lipogenesis and fatty acid β‐oxidation. Results PTPRO expression was notably downregulated in CRC liver metastasis compared to the primary cancer, and such a downregulation was associated with poor prognosis of patients with CRC. PTPRO silencing significantly promoted cell growth and liver metastasis. Compared with PTPRO wild‐type mice, PTPRO‐knockout mice developed more tumors and harbored larger tumor loads under treatment with azoxymethane and dextran sulfate sodium. Gene set enrichment analysis revealed that PTPRO downregulation was significantly associated with the fatty acid metabolism pathways. Blockage of fatty acid synthesis abrogated the effects of PTPRO silencing on cell growth and liver metastasis. Further experiments indicated that PTPRO silencing induced the activation of the AKT serine/threonine kinase (AKT)/mammalian target of rapamycin (mTOR) signaling axis, thus promoting de novo lipogenesis by enhancing the expression of sterol regulatory element‐binding protein 1 (SREBP1) and its target lipogenic enzyme acetyl‐CoA carboxylase alpha (ACC1) by activating the AKT/mTOR signaling pathway. Furthermore, PTPRO attenuation decreased the fatty acid oxidation rate by repressing the expression of peroxisome proliferator‐activated receptor alpha (PPARα) and its downstream enzyme peroxisomal acyl‐coenzyme A oxidase 1 (ACOX1) via activating the p38/extracellular signal‐regulated kinase (ERK) mitogen‐activated protein kinase (MAPK) signaling pathway. Conclusions PTPRO could suppress CRC development and metastasis via modulating the AKT/mTOR/SREBP1/ACC1 and MAPK/PPARα/ACOX1 pathways and reprogramming lipid metabolism.
Clinical images: Giant intraosseous synovial cyst with intraarticular connection at the elbow in rheumatoid arthritis
Authors: Can M. Sungur, Jonathan C. Baker
Journal: Arthritis & Rheumatology (2022)

Disclosure Form Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.